Mené en Chine sur 26 patients atteints d'un cancer non à petites cellules et de stade localement avancé de la région périphérique du poumon (durée médiane de suivi : 28 mois), cet essai de phase I évalue la sécurité et la faisabilité d'un traitement combinant une curiethérapie interstitielle à haut débit de dose guidée par tomographie numérique et une radiothérapie avec modulation d'intensité ciblant les ganglions régionaux atteints

CT- guided Interstitial 3D After-loading Radiotherapy in Combination with Regional Positive Lymph Nodes Intensity Modulated Radiotherapy(IMRT) in Patients with Locally Advanced Peripheral Non-small cell Lung Cancer(NSCLC): A Phase I Clinical Trail

Xiang, Li ; Zhang, Jian-wen ; Lin, Sheng ; Luo, Hui-Qun ; Wen, Qing-Lian ; He, Li-Jia ; Shang, Chang-Ling ; Ren, Pei-Rong ; Yang, Hong-Ru ; Pang, Hao-Wen ; Yang, Bo ; He, Huai-Lin ; Chen, Yue ; Wu, Jing-Bo

Purpose : To assess the technical safety, complications, and efficacy of computed tomography (CT)-guided interstitial high-dose-rate (HDR) brachytherapy in combination with regional positive lymph node intensity-modulated radiotherapy in patients with locally advanced peripheral non-small cell lung cancer (NSCLC). Methods and Materials : Twenty-six patients with histologically confirmed NSCLC were enrolled in a prospective, officially approved phase I trial. Primary tumors were treated via HDR [...]

Cet article passe en revue les études concernant l'efficacité et la toxicité d'une radiothérapie ablative stéréotaxique pour traiter une tumeur du poumon ayant récidivé après une radiothérapie thoracique à haute dose de rayonnements ionisants

Available Evidence on Re-Irradiation with Stereotactic Ablative Radiotherapy Following High-dose Previous Thoracic Radiotherapy for Lung Malignancies

De Bari, Berardino ; Filippi, Andrea Riccardo ; Mazzola, Rosario ; Bonomo, Pierluigi ; Trovò, Marco ; Livi, Lorenzo ; Alongi, Filippo

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. [...]

Menée à partir de données portant sur 85 patients atteints d'un sarcome des tissus mous des mains et des pieds et traités entre 1966 et 2012 (âge médian au diagnostic : 41 ans ; durée médiane de suivi : 140 mois), cette étude évalue, du point de vue des taux de contrôle local, de survie sans maladie et de survie globale à 5 ans, l'efficacité d'une chirurgie épargnant les membres en combinaison avec une radiothérapie

Combined limb-sparing surgery and radiation therapy to treat sarcomas of the hands and feet: long-term cancer outcomes and morbidity

Bishop, Andrew J. ; Zagars, Gunar K. ; Moon, Bryan S. ; Lin, Patrick P. ; Lewis, Valerae O. ; Guadagnolo, B. Ashleigh

Purpose : To investigate local control, survival outcomes, and complication rates of patients treated with limb-sparing surgery and radiation therapy (RT) for soft-tissue sarcomas (STS) of the hands and feet. Methods : We reviewed the medical records of 85 consecutive patients treated for STS of the hands (n=38, 45%) and feet (n=47, 55%) between 1966 and 2012. The median age was 41 years (range, 10-82 years). Sixty-seven patients (79%) received postoperative RT after resection of their tumor [...]

A partir d'une revue systématique de la littérature publiée entre 1990 et 2013 (59 articles, 13 396 patients atteints d'un cancer de la vessie), cette étude compare, du point de vue du taux de survie globale à 5 ans, l'efficacité d'une cystectomie radicale et d'un traitement conservateur comportant une résection transurétrale de la tumeur, puis une chimiothérapie en combinaison avec une radiothérapie concomitante

Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer : a systematic review of clinical trials

Arcangeli, G. ; Strigari, L. ; Arcangeli, S.

Background : Radical cystectomy (RC) represents the mainstay of treatment in patients with muscle-invasive urinary bladder cancer but how it compares with the best organ preservation approach is not known. Materials and methods : The objective of our review is to compare 5-year overall survival (OS) rates from retrospective and prospective studies of RC and trimodality treatment (TMT), i.e. concurrent delivery of chemotherapy and radiotherapy after a transurethral resection of bladder tumor [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes associés à l'apparition d'une résistance au sorafénib dans le traitement d'un carcinome hépatocellulaire

Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma

Kuczynski, Elizabeth A ; Lee, Christina R. ; Man, Shan ; Chen, Eric ; Kerbel, Robert S

Acquired evasive resistance is a major limitation of hepatocellular carcinoma (HCC) treatment with the tyrosine kinase inhibitor (TKI) sorafenib. Recent findings suggest that resistance to sorafenib may have a reversible phenotype. Additionally, loss of responsiveness has been proposed to be due to a gradual decrease in sorafenib plasma levels in patients. Here, the possible mechanisms underlying reversible sorafenib resistance were investigated using a Hep3B-hCG orthotopic human xenograft [...]

Cet article passe en revue les perspectives offertes par les anticorps monoclonaux anti CD137 pour le développement d'immunothérapies anticancéreuses en combinaison

Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy

Yonezawa, Atsushi ; Dutt, Suparna ; Chester, Cariad ; kim, Jeewon ; Kohrt, Holbrook E.

In the last five years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing anti-tumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4+ T cells, CD8+ T cells, dendritic cells and natural killer cells. Recent studies indicate that the anti-tumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition [...]

Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un vaccin thérapeutique personnalisé à base d'ARNs messagers synthétiques

Mutant MHC class II epitopes drive therapeutic immune responses to cancer

Kreiter, Sebastian ; Vormehr, Mathias ; van de Roemer, Niels ; Diken, Mustafa ; Lower, Martin ; Diekmann, Jan ; Boegel, Sebastian ; Schrors, Barbara ; Vascotto, Fulvia ; Castle, John C. ; Tadmor, Arbel D. ; Schoenberger, Stephen P. ; Huber, Christoph ; Tureci, Ozlem ; Sahin, Ugur

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient’s tumour possesses a unique set of mutations (‘the mutanome’) that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient’s [...]

Menée in vitro et in vivo sur des modèles de cancer du poumon non à petites cellules et des modèles de cancer de l'ovaire, cette étude évalue l'activité antitumorale d'un conjugué anticorps-médicament (IMGN853) ciblant le récepteur alpha des folates

IMGN853, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, exhibits potent targeted anti-tumor activity against FRα-expressing tumors

Ab, Olga ; Whiteman, Kathleen R. ; Bartle, Laura M ; Sun, Xiuxia ; Singh, Rajeeva ; Tavares, Daniel ; LaBelle, Alyssa ; Payne, Gillian ; Lutz, Robert J ; Pinkas, Jan ; Goldmacher, Victor S. ; Chittenden, Thomas ; Lambert, John M

A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here we report the development of an anti-FRα antibody drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody, M9346A as the best antibody for targeted delivery of a [...]

Menée sur des lignées cellulaires de lymphome, cette étude met en évidence des mutations associées au développement d'une résistance à un inhibiteur de la méthyltransférase EZH2

Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors

Gibaja, V. ; Shen, F. ; Harari, J. ; Korn, J. ; Ruddy, D. ; Saenz-Vash, V. ; Zhai, H. ; Rejtar, T. ; Paris, C. G. ; Yu, Z. ; Lira, M. ; King, D. ; Qi, W. ; Keen, N. ; Hassan, A. Q. ; Chan, H. M.

The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is frequently dysregulated in cancers, and gain-of-function (GOF) EZH2 mutations have been identified in non-Hodgkin lymphomas. Small-molecule inhibitors against EZH2 demonstrated anti-tumor activity in EZH2-mutated lymphomas and entered clinical trials. Here, we developed models of acquired resistance to EZH2 inhibitor EI1 with EZH2-mutated lymphoma cells. Resistance was generated by secondary mutations in both wild-type (WT) and [...]

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé MM-151 qui associe 3 anticorps monoclonaux ciblant des épitopes différents du récepteur EGFR

Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-EGFR antibody therapeutic

Kearns, Jeffrey D ; Bukhalid, Raghida ; Sevecka, Mark ; Tan, Gege ; Gerami-Moayed, Nastaran ; Werner, Shannon L ; Kohli, Neeraj ; Burenkova, Olga ; Sloss, Callum M ; King, Anne M ; Fitzgerald, Jonathan B ; Nielsen, Ulrik B ; Wolf, Beni B

While epidermal growth factor receptor (EGFR) is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly co-expressed with low-affinity EGFR ligands in [...]

Cet article passe en revue les enjeux associés à l'hétérogénéité intratumorale pour la prise en charge thérapeutique des patientes atteintes d'un cancer du sein

Clinical management of breast cancer heterogeneity

Zardavas, Dimitrios ; Irrthum, Alexandre ; Swanton, Charles ; Piccart, Martine

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. Results of high-throughput molecular profiling studies have subsequently revealed the true extent of this heterogeneity. Further complicating this scenario, the heterogeneous expression of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 has been reported in different areas of [...]

Cet article passe en revue les travaux récents sur l'intérêt des analyses génomiques pour le traitement des patients atteints d'un carcinome épidermoïde de la tête et du cou

Integrating genomics in head and neck cancer treatment: promises and pitfalls

Thariat, Juliette ; Vignot, Stéphane ; Lapierre, Ariane ; Falk, Alexander T. ; Guigay, Joël ; Van Obberghen-Schilling, Ellen ; Milano, Gérard

Head and neck squamous cell carcinomas (HNSCC) represent a multifactorial disease of poor prognosis. They have lagged behind other cancers in terms of personalized therapy. With expansion and high throughput sequencing methods, recent landmark exonic studies and Cancer Genome Atlas data have identified genes relevant to carcinogenesis and cancer progression. Mutational profiles and rates vary widely depending on exposure to carcinogens, anatomic subsites and human papilloma virus (HPV) [...]

Cet article passe en revue les travaux récents sur les effets indésirables associés aux nouvelles immunothérapies anticancéreuses

Toxicities of Immunotherapy for the Practitioner

Weber, Jeffrey S. ; Yang, James C. ; Atkins, Michael B. ; Disis, Mary L.

The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune [...]

A partir d'une revue systématique de la littérature (50 articles identifiés), cette étude analyse la qualité des informations relatives aux événements indésirables de nature immunitaire dans les publications portant sur des essais cliniques d'évaluation d'inhibiteurs des points de contrôle immunitaire (CTLA-4 et autres)

A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors

Chen, T.W. ; Razak, A. R. ; Bedard, P. L. ; Siu, L. L. ; Hansen, A. R.

Background There are limited data about the quality of immune related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications. Methods A systematic search of citations from MEDLINE, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003-2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with [...]

Mené sur 268 patients adultes atteints d'une leucémie lymphoblastique aiguë Ph+, cet essai randomisé franco-suisse évalue l'efficacité, du point de vue du taux de réponse moléculaire majeure, d'un traitement d'induction combinant une chimiothérapie d'intensité réduite et l'imatinib

Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia

Chalandon, Yves ; Thomas, Xavier ; Hayette, Sandrine ; Cayuela, Jean-Michel ; Abbal, Claire ; Huguet, Françoise ; Raffoux, Emmanuel ; Leguay, Thibaut ; Rousselot, Philippe ; Lepretre, Stephane ; Escoffre-Barbe, Martine ; Maury, Sebastien ; Berthon, Céline ; Tavernier, Emmanuelle ; Lambert, Jean-François ; Lafage-Pochitaloff, Marina ; Lhéritier, Véronique ; Chevret, Sylvie ; Ifrah, Norbert ; Dombret, Hervé

Initial imatinib-based therapy of Ph-positive adult ALL is associated with lower early mortality and higher CR rate.In adults with Ph+ ALL, allo-SCT in CR1 prolongs RFS and OS, even if some favorable patients may have a similar outcome after auto-SCT. In this study, we randomly compared high doses of the tyrosine kinase inhibitor (TKI) imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/HyperCVAD treatment (arm B) in 268 adults (median age, 47 years) with [...]

Mené sur 28 patients atteints d'un lymphome hodgkinien réfractaire ou récidivant, cet essai de phase I évalue la dose maximale tolérée, la toxicité et l'activité antitumorale d'un anticorps bispécifique anti-CD30/CD16A

A phase I study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

Rothe, Achim ; Sasse, Stephanie ; Topp, Max S. ; Eichenauer, Dennis A. ; Hummel, Horst ; Reiners, Katrin S. ; Dietlein, Markus ; Kuhnert, Georg ; Kessler, Joerg ; Buerkle, Carolin ; Ravic, Miroslav ; Knackmuss, Stefan ; Marschner, Jens-Peter ; Pogge von Strandmann, Elke ; Borchmann, Peter ; Engert, Andreas

The bispecific, tetravalent antibody AFM13 represents a new approach engaging natural killer cells via CD16A to fight CD30+ malignancies.AFM13 is well tolerated and active in Hodgkin lymphoma patients who received all standard therapies including brentuximab vedotin. AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA®) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this [...]

Menée sur 102 patients atteints d'un mélanome traité à l'aide d'un inhibiteur de BRAF (vémurafénib ou dabrafénib), cette étude met en évidence un risque de lymphopénie associé à une administration combinée de dexaméthasone

Corticosteroids Augment BRAF Inhibitor Vemurafenib Induced Lymphopenia and Risk of Infection

Sondermann, Wiebke ; Griewank, Klaus G. ; Schilling, Bastian ; Livingstone, Elisabeth ; Leyh, Julia C. ; Rompoti, Natalia ; Cosgarea, Ioana ; Schimming, Tobias ; Schadendorf, Dirk ; Zimmer, Lisa ; Hillen, Uwe

We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids [...]

Mené sur 834 patients atteints d'un mélanome avancé, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité du prembrolizumab par rapport à l'ipilimumab

Pembrolizumab versus Ipilimumab in Advanced Melanoma

Robert, Caroline ; Schachter, Jacob ; Long, Georgina V. ; Arance, Ana ; Grob, Jean Jacques ; Mortier, Laurent ; Daud, Adil ; Carlino, Matteo S. ; McNeil, Catriona ; Lotem, Michal ; Larkin, James ; Lorigan, Paul ; Neyns, Bart ; Blank, Christian U. ; Hamid, Omid ; Mateus, Christine ; Shapira-Frommer, Ronnie ; Kosh, Michele ; Zhou, Honghong ; Ibrahim, Nageatte ; Ebbinghaus, Scot ; Ribas, Antoni

BACKGROUND : The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS : In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or [...]

Mené sur 142 patients atteints d'un mélanome métastatique, cet essai en double aveugle évalue l'efficacité, du point de vue du taux de réponse objective chez les patients dont les tumeurs ne présentant pas la mutation V600E du gène BRAF, et la toxicité de l'ajout du nivolumab à l'ipilimumab en traitement de première ligne

Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma

Postow, Michael A. ; Chesney, Jason ; Pavlick, Anna C. ; Robert, Caroline ; Grossmann, Kenneth ; McDermott, David ; Linette, Gerald P. ; Meyer, Nicolas ; Giguere, Jeffrey K. ; Agarwala, Sanjiv S. ; Shaheen, Montaser ; Ernstoff, Marc S. ; Minor, David ; Salama, April K. ; Taylor, Matthew ; Ott, Patrick A. ; Rollin, Linda M. ; Horak, Christine ; Gagnier, Paul ; Wolchok, Jedd D. ; Hodi, F. Stephen

BACKGROUND : In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS : In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with [...]

Mené sur 245 patients atteints d'un mélanome non résécable de stade III ou IV, cet essai randomisé de phase II évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout de sargramostim à l'ipilimumab (durée médiane de suivi : 13,3 mois)

Combination immunotherapy for melanoma

Kaufman, H. L.

Importance : Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. Objective : To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on [...]

Cet article passe en revue les travaux récents sur le développement de thérapies ciblées et d'immunothérapies pour le traitement des patients atteints d'un mélanome métastatique

Therapeutic advances and treatment options in metastatic melanoma

Johnson, D. B. ; Sosman, J. A.

Over the past several years, management of advanced melanoma has been transformed by the development and approval of novel therapeutic approaches. Genetically targeted therapies are now effective treatment options for the approximately 50% of patients whose melanomas harbor activating point mutations in BRAF. Combination regimens of small-molecule inhibitors have been developed to delay the onset of acquired resistance. Specifically, combined BRAF and MEK inhibition improves response rates and [...]

Menée sur 23 patients traités à l'aide de vémurafénib pour un mélanome métastatique non résécable présentant la mutation V600E du gène BRAF, cette étude française analyse l'évolution de la concentration plasmatique du vémurafénib en association avec la progression tumorale

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance

Funck-Brentano, E. ; Alvarez, J.C. ; Longvert, C. ; Abe, E. ; Beauchet, A. ; Funck-Brentano, C. ; Saiag, P.

Background : Vemurafenib improves survival in advanced BRAFV600mut melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. Methods : Plasma samples from unresectable metastatic BRAFV600mut melanoma patients treated with vemurafenib monotherapy, were prospectively collected at each tumour response evaluation [...]

Mené sur 129 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai évalue l'efficacité, du point de vue de la survie globale, et la toxicité du nivolumab

Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

Gettinger, Scott N. ; Horn, Leora ; Gandhi, Leena ; Spigel, David R. ; Antonia, Scott J. ; Rizvi, Naiyer A. ; Powderly, John D. ; Heist, Rebecca S. ; Carvajal, Richard D. ; Jackman, David M. ; Sequist, Lecia V. ; Smith, David C. ; Leming, Philip ; Carbone, David P. ; Pinder-Schenck, Mary C. ; Topalian, Suzanne L. ; Hodi, F. Stephen ; Sosman, Jeffrey A. ; Sznol, Mario ; McDermott, David F. ; Pardoll, Drew M. ; Sankar, Vindira ; Ahlers, Christoph M. ; Salvati, Mark ; Wigginton, Jon M. ; Hellmann, Matthew D. ; Kollia, Georgia D. ; Gupta, Ashok K. ; Brahmer, Julie R.

Purpose : Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and [...]

Mené sur 495 patients atteints d'un cancer du poumon de stade avancé, cet essai de phase I évalue l'activité antitumorale et la toxicité du pembrolizumab en fonction du niveau d'expression de PD-L1

Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

Garon, Edward B. ; Rizvi, Naiyer A. ; Hui, Rina ; Leighl, Natasha ; Balmanoukian, Ani S. ; Eder, Joseph Paul ; Patnaik, Amita ; Aggarwal, Charu ; Gubens, Matthew ; Horn, Leora ; Carcereny, Enric ; Ahn, Myung-Ju ; Felip, Enriqueta ; Lee, Jong-Seok ; Hellmann, Matthew D. ; Hamid, Omid ; Goldman, Jonathan W. ; Soria, Jean-Charles ; Dolled-Filhart, Marisa ; Rutledge, Ruth Z. ; Zhang, Jin ; Lunceford, Jared K. ; Rangwala, Reshma ; Lubiniecki, Gregory M. ; Roach, Charlotte ; Emancipator, Kenneth ; Gandhi, Leena

BACKGROUND : We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS : We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram [...]

Mené au Japon sur 387 patients atteints d'un cancer colorectal métastatique, cet essai randomisé multicentrique de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité de deux doses de bévacizumab en combinaison avec une chimiothérapie FOLFIRI pour un traitement de deuxième ligne

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

Iwamoto, S. ; Takahashi, T. ; Tamagawa, H. ; Nakamura, M. ; Munemoto, Y. ; Kato, T. ; Hata, T. ; Denda, T. ; Morita, Y. ; Inukai, M. ; Kunieda, K. ; Nagata, N. ; Kurachi, K. ; Ina, K. ; Ooshiro, M. ; Shimoyama, T. ; Baba, H. ; Oba, K. ; Sakamoto, J. ; Mishima, H.

Background : A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. Patient and Methods : Patients were randomized to receive FOLFIRI plus bevacizumab 5 mg/kg or 10 mg/kg in 2-week cycles [...]

Mené sur 71 patients adultes atteints d'un sarcome des tissus mous de stade avancé, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du temsirolumus au sélumétinib

A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas

Eroglu, Z. ; Tawbi, H. A. ; Hu, J. ; Guan, M. ; Frankel, P. H. ; Ruel, N. H. ; Wilczynski, S. ; Christensen, S. ; Gandara, D. R. ; Chow, W. A.

Background: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. Methods: Seventy-one adults with advanced STS [...]

Mené sur 58 patients atteints d'un cancer différencié de la thyroïde de stade avancé et réfractaire à l'iode radioactif, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du lenvatinib (durée de suivi supérieure à 14 mois)

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment

Cabanillas, Maria E. ; Schlumberger, Martin ; Jarzab, Barbara ; Martins, Renato G. ; Pacini, Furio ; Robinson, Bruce ; McCaffrey, Judith C. ; Shah, Manisha H. ; Bodenner, Donald L. ; Topliss, Duncan ; Andresen, Corina ; O'Brien, James P. ; Ren, Min ; Funahashi, Yasuhiro ; Allison, Roger ; Elisei, Rossella ; Newbold, Kate ; Licitra, Lisa F. ; Sherman, Steven I. ; Ball, Douglas W.

BACKGROUND : Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients [...]

Menée à l'aide d'une xénogreffe de leucémie lymphoblastique agressive à précurseurs B sur un modèle murin, cette étude montre qu'une composition liposomale renfermant un inhibiteur du site P des tyrosines kinases exprimées dans la moelle osseuse peut augmenter l'efficacité d'une irradiation corporelle totale à faible dose de rayonnements ionisants

Liposomal Nanoparticles of a Spleen Tyrosine Kinase P-Site Inhibitor Amplify the Potency of Low Dose Total Body Irradiation Against Aggressive B-Precursor Leukemia and Yield Superior Survival Outcomes in Mice

Uckun, Fatih M. ; Myers, Dorothea E. ; Cheng, Jianjun ; Qazi, Sanjive

This study was designed to improve the efficacy of radiation therapy against radiation-resistant leukemia. We report that the potency of low dose radiation therapy against B-precursor acute lymphoblastic leukemia (BPL) can be markedly enhanced by combining radiation with a liposomal nanoparticle (LNP) formulation of the SYK-P-site inhibitor C61 (?C61-LNP?). C61-LNP plus low dose total body irradiation (TBI) was substantially more effective than TBI alone or C61-LNP alone in improving the [...]

Menée à partir de données portant sur 257 patients atteints d'un lymphome hodgkinien de stade I-IIAB (durée médiane de suivi : 56 mois), cette étude montre que prolonger une chimiothérapie et lui ajouter une radiothérapie peut permettre une rémission complète durable chez les patients présentant une maladie résiduelle (détectée par tomographie numérique par émission de positrons à base de fluorodésoxyglucose) après deux cycles de chimiothérapie par ABVD

The continuation of chemotherapy followed by radiation may obtain durable complete remission in early stage Hodgkin Lymphoma patients with a positive FDG-Positron Emission Tomography after the first two ABVD Cycles

Simontacchi, Gabriele ; Filippi, Andrea Riccardo ; Ciammella, Patrizia ; Buglione, Michela ; Saieva, Calogero ; Magrini, Stefano Maria ; Livi, Lorenzo ; Iotti, Cinzia ; Botto, Barbara ; Vaggelli, Luca ; Re, Alessandro ; Merli, Francesco ; Ricardi, Umberto

Purpose : This multicenter retrospective study was designed with the aims to: a) evaluate the prognostic role of interim-FDG-PET (i-FDG-PET) in a cohort of patients affected with early stage HL treated upfront with ABVD chemotherapy followed by radiotherapy, and b) assess the role of chemotherapy continuation plus radiotherapy for i-FDG-PET positive patients. Methods and Materials : data of 257 patients were retrieved from 4 Hematology/Radiation Oncology Departments. Inclusion criteria were: [...]

Mené sur 602 patients atteints d'un lymphome hodgkinien de stade IA ou IIA (âge médian : 34 ans ; durée médiane de suivi : 60 mois), cet essai évalue, du point de vue du taux de survie sans progression à 3 ans, l'intérêt d'ajouter une radiothérapie de consolidation à trois cycles de chimiothérapie de type ABVD chez les patients dont la tomographie numérique par émission de positrons, réalisée après la chimiothérapie, n'a révélé aucune malignité

Results of a Trial of PET-Directed Therapy for Early-Stage Hodgkin’s Lymphoma

Radford, John ; Illidge, Tim ; Counsell, Nicholas ; Hancock, Barry ; Pettengell, Ruth ; Johnson, Peter ; Wimperis, Jennie ; Culligan, Dominic ; Popova, Bilyana ; Smith, Paul ; McMillan, Andrew ; Brownell, Alison ; Kruger, Anton ; Lister, Andrew ; Hoskin, Peter ; O’Doherty, Michael ; Barrington, Sally

Background : It is unclear whether patients with early-stage Hodgkin’s lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. Methods : Patients with newly diagnosed stage IA or stage IIA Hodgkin’s lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field [...]

Mené sur 794 patients atteints d'un lymphome hodgkinien médiastinal bourgeonnant de stade 1 ou 2 (durée médiane de suivi : 6,5 ans), cet essai de phase III compare, du point de vue du taux de réponse globale, de survie sans échec thérapeutique et de survie globale à 5 ans, l'efficacité d'une chimiothérapie par ABVD et d'une chimiothérapie de type Stanford V en combinaison avec une radiothérapie du champ impliqué

Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial

Advani, Ranjana H. ; Hong, Fangxin ; Fisher, Richard I. ; Bartlett, Nancy L. ; Robinson, K. Sue ; Gascoyne, Randy D. ; Wagner, Henry ; Stiff, Patrick J. ; Cheson, Bruce D. ; Stewart, Douglas A. ; Gordon, Leo I. ; Kahl, Brad S. ; Friedberg, Jonathan W. ; Blum, Kristie A. ; Habermann, Thomas M. ; Tuscano, Joseph M. ; Hoppe, Richard T. ; Horning, Sandra J.

Purpose : The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL). Patients and Methods : [...]

Menée sur des cellules humaines de cancer du côlon ou du poumon et à l'aide de xénogreffes sur des modèles murins, cette étude montre que le daurinol (connu comme inhibiteur de l'ADN topo-isomérase) augmente, en supprimant l'expression des kinases Aurora A et B, l'efficacité de la radiothérapie

Daurinol enhances the efficacy of radiation therapy in lung cancer via suppression of aurora kinase A/B expression

Woo, Jong Kyu ; Kang, Ju-Hee ; Shin, DongYun ; Park, Seong-Hyeok ; Kang, Kyungsu ; Nho, Chu Won ; Seong, Je Kyung ; Lee, Sang-Jin ; Oh, Seun Hyun

The aurora kinases constitute one family of serine / threonine kinases whose activity is essential for mitotic progression. The aurora kinases are frequently up-regulated in human cancers, and are associated with sensitivity to chemotherapy in certain ones. In the present study, we investigated whether aurora kinases could be a target to overcome radioresistance or enhance the radiosensitivity of lung cancer. For that purpose, we determined the therapeutic potential of daurinol, an [...]

Mené sur 114 patients atteints d'un glioblastome récemment diagnostiqué, cet essai multicentrique de phase II évalue, du point de vue de la survie globale, de la survie sans progression et de la toxicité, l'intérêt d'ajouter le vandétanib à un traitement combinant une radiothérapie et le témozolomide

A multicenter, phase II, randomized, non-comparative clinical trial of radiation and temozolomide with or without vandetanib in newly-diagnosed glioblastoma patients

Lee, Eudocia Q ; Kaley, Thomas J ; Duda, Dan G ; Schiff, David ; Lassman, Andrew B. ; Wong, Eric T ; Mikkelsen, Tom ; Purow, Benjamin ; Muzikansky, Alona ; Ancukiewicz, Marek ; Huse, Jason T. ; Ramkissoon, Shakti H ; Drappatz, Jan ; Norden, Andrew D ; Beroukhim, Rameen ; Weiss, Stephanie E ; Alexander, Brian Michael ; McCluskey, Christine S. ; Gerard, Mary ; Smith, Katrina H ; Jain, Rakesh K ; Batchelor, Tracy ; Ligon, Keith L ; Wen, Patrick Y.

Purpose : Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, non-comparative, phase II study of radiation (RT) and temozolomide (TMZ) with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). Experimental Design : We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and TMZ with (76 patients) or without (38 patients) [...]

A partir d'une revue de la littérature rapportant les résultats d'essais randomisés de phase III pour le traitement d'une tumeur solide (212 articles identifiés entre janvier 2001 et fin 2013), cette étude évalue la qualité des informations relatives aux analyses en sous-groupes

Subgroup Analyses in Reporting of Phase III Clinical Trials in Solid Tumors

Zhang, Sheng ; Liang, Fei ; Li, Wenfeng ; Hu, Xichun

Purpose : Treatment decisions in clinical oncology are guided by results from phase III randomized clinical trials (RCTs). The results of subgroup analyses may be potentially important in individualizing patient care. We investigated the appropriateness of the use and interpretation of subgroup analyses in oncology RCTs on the basis of the CONSORT statement requirements. Methods : Phase III RCTs published between January 1, 2011, and December 31, 2013, were reviewed to identify eligible studies [...]

Cet article passe en revue les obstacles à franchir pour mener des essais cliniques internationaux évaluant des traitements personnalisés chez des patients atteints d'un cancer

Challenges in Initiating and Conducting Personalized Cancer Therapy Trials: Perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium Trial

Rodon, J. ; Soria, J.C. ; Berger, R. ; Batist, G. ; Tsimberidou, A. ; Bresson, C. ; Lee, J.J. ; Rubin, E. ; Onn, A. ; Schilsky, R.L. ; Miller, W.H. ; Eggermont, A.M. ; Mendelsohn, J. ; Lazar, V. ; Kurzrock, R.

Advances in “omics” technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting-edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multi-national trial (five [...]

Cet article passe en revue les raisons expliquant le nombre limité d'essais cliniques en matière de chirurgie oncologique puis présente des solutions pouvant y remédier

The future of trials in surgical oncology

Naredi, Peter ; La Quaglia, Michael P.

Patients with cancer generally have better outcomes when treated as part of a clinical trial compared with patients not enrolled in a clinical trial. Unfortunately, surgical participation in, and leadership of such studies, is limited. This lack of clinical investigation is adversely affecting progress in cancer surgery research and, ultimately, hinders the treatment of patients. Some of the reasons for poor surgical participation in clinical research include: limitations on funding provision; [...]